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Organophosphorus pesticides – and in particular chlorpyrifos (CPF) – are extensively used worldwide. They mainly exert their toxicity by targeting the cholinergic system. Several studies suggested that the gene coding for apolipoprotein E (apoE), which is a risk factor for several diseases, can also confer different vulnerability to toxic insults. This study was aimed at assessing the long-term effects of postnatal exposure to CPF on learning and memory as well as the expression levels of several genes involved in cholinergic neurotransmission in mice. Both male and female apoE4-TR and C57BL/6 mice were exposed to either 0 or 1 mg/kg/day of CPF by oral gavage using a micropipette on postnatal days 10–15. At 9 months, they were tested in a Morris Water Maze (MWM) and the gene expression in the frontal cortex and hippocampus was evaluated. Our results show that, in males, CPF had an effect on the spatial retention, while in females, it altered the expression levels of nicotinic receptors. Furthermore, apoE4-TR mice performed the worst during the MWM retention and presented low expression levels in a considerable number of cholinergic genes. Taken together, the current results reveal long-term effects in mice nine months after postnatal exposure to CPF, which are modulated by sex and apoE4 genotype.

Chlorpyrifos (CPF) is one of the most commonly used organophosphate pesticides in the world. Our previous results described that apolipoprotein E (APOE) polymorphisms are a source of individual differences in susceptibility to CPF. The aim of this study was to assess the physical and biochemical effects of postnatal exposure to CPF in the apoE targeted replacement mouse model. Mice were exposed to CPF at 0 or 1 mg/kg/day from postnatal day 10–15. Physical development, plasma and forebrain cholinesterase (ChE) activity and gene expression in liver and forebrain were evaluated. CPF exposure delays physical maturation and decreases the expression of choline acetyltransferase, α4-subunit and the α7 receptor. CPF decreases the expression of vesicular acetylcholine transporter (VAChT) mRNA in the forebrain only in apoE3 mice. The expression of paraoxonase-2 in the forebrain was also influenced by APOE genotype and CPF. Differences between genotypes were observed in litter size, ChE activity, expression of butyrylcholinesterase and paraoxonase-1 in liver and variants of acetylcholinesterase, VAChT and the α7 receptor in the forebrain. These results support that there are different vulnerabilities to postnatal CPF exposure according to the APOE polymorphism, which in turn affects the cholinergic system and defenses to oxidative stress.

Chlorpyrifos (CPF) is an organophosphorus pesticide widely and extensively used in agriculture in more than one hundred countries and found ubiquitously in the environment. The present study was aimed at providing a better understanding of the obesogenic potential of CPF and its metabolites, as well as to evaluate their effects on the adipocyte differentiation process. For it, during the initial differentiation process, 3T3-L1 mouse preadipocytes were exposed to different concentrations of CPF, CPF-oxon (CPO), or 3,5,6-trichloropyridinol (TCP), which did not affect cell survival. Results showed how CPF and, to a lesser extent, its metabolite TCP, had a positive metabolic influence over the adipogenic process by fostering an increase in the number of differentiated 3T3-L1 preadipocytes, and by enhancing the capacity to store lipid droplets. These processes seem to occur through the upregulation of the transcription factors CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which are related to a significant higher expression of the fatty acid-binding protein 4 (FABP4) adipokine. Based on this finding, CPF exposure could be one of the many factors that contributes to the worldwide increase in the incidence of obesity. However, additional investigations are clearly needed.

Development is especially sensitive to Chlorpyrifos (CPF) toxicity, associated with several neurodegenerative and neurodevelopmental disorders where motor function dysfunction is a core symptom. Amongst the alternative molecular targets to cholinesterases inhibition, developmental CPF alters different components in the most important neurotransmitter systems, although this depends on the exposure period. Exposure during the late postnatal preweaning stage is the least studied by far. This period includes essential neurodevelopmental processes and has an important translational meaning. The present study analyzed the influence of low doses of CPF on this developmental window on locomotor activity and the state of the different neurotransmitter systems by pharmacological challenges. Brain gene expression and microbiome modulation following CPF were also analyzed. CPF exposure long-term increased spontaneous vertical activity, female's activity following acute stress, hyposensitized the cholinergic system and hypersensitized the GABAergic system, up-regulated both muscarinic 2 receptor and GABA-A-α2 receptor subunit in the dorsal striatum and the frontal cortex, respectively and induced gut microbiota dysbiosis at both genus and species levels. The present study supports alternative molecular targets than the ChEs following late postnatal, preweaning exposure to low doses of CPF, focusing on both cholinergic and GABAergic systems and the gut microbiome as an important factor.

The gut microbiota comprises a large number of microorganisms, whose composition can be modified by genetic and environmental factors. The host's genetic background, including the different isoforms of the apolipoprotein E (APOE) gene, can exert an influence over microbiota composition. Exposure to the widely-used pesticide chlorpyrifos (CPF), can lead to dysbiosis and alter the levels of metabolites produced by the microbiota, such as short-chain fatty acids (SCFAs). This study was aimed at assessing the contribution of the APOE genotype and early exposure to CPF on gut microbiota and SCFA in brain. For it, C57BL/6, apoE3-and apoE4-TR mice were orally exposed to CPF from postnatal day (PND) 10 to PND 15. Microbiota in the gut and SCFA in the brain were assessed at PND 15 after CPF exposure. Differences between genotypes at different taxonomic levels were found, A. muciniphila presented greater abundance in APOE4 genotype, but was reduced by CPF exposure. APOE and CPF influenced cerebral SCFAs, with APOE3 genotype showing the highest levels of acetic, propionic and butyric acids and CPF exposure inducing the highest levels of isovaleric and 4-methylvaleric acids. These results provide further knowledge about gut microbiota and cerebral SCFAs composition at early ages and their modulation by APOE and postnatal CPF exposure.

In this study, we examined the effects of an oral subacute exposure to 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) on young adult inbred wild type Tg2576 mice. BDE-209 was administered by gavage at doses of 0 and 20 mg/kg/day dissolved in sunflower oil for 15 days. Two behavioral endpoints were examined: anxiety-activity in a light/dark test and a zero maze test, and learning and spatial memory in a water maze test. Young adult mice exposed to BDE-209 showed a reduction in anxiety levels and a delayed learning in a spatial memory task. Although the results indicated that behavioral effects were present in a young adult exposed population of wild type Tg2576 mice, further studies on chronic exposure to BDE-209 are clearly necessary in order to corroborate these effects.

Reproduction studies were performed with gallium nitrate, an antihypercalcaemic drug that is also used as a chemotherapeutic agent for the treatment of certain malignancies. Male mice were injected subcutaneously with gallium nitrate at doses of 0 (controls), 24, 48 and 96 mg/kg/day every other day for 14 days before mating with untreated females. Fertility and reproductive performance in the gallium nitrate-treated groups did not differ significantly from controls. No significant changes were observed in the relative testes and epididymis weights. Sperm counts in the gallium nitrate-dosed groups were comparable with those in the control group, whereas the percentage of motile cells was similar between treated and untreated animals. Histopathological examination of the testes and epididymis did not reveal any changes at any dose of gallium nitrate. The no-observed-adverse effect level was 96 mg/kg body weight. This dose is about 30 times higher than the current doses of gallium nitrate administered to humans.